CN107073221A - From the distributor for puncturing liquid medicine kit and correlation - Google Patents

Abstract

Self-piercing liquid drug cartridges and associated inhalers are used to deliver one or more individual doses of aerosolized liquid drug. The liquid drug cartridge includes a needle assembly coupled to a drug container. The needle assembly includes a hollow needle and is reconfigurable from a first configuration to a second configuration when the cartridge is inserted into the inhaler. In the first configuration, the hollow needle does not extend into the container. In the second configuration, the hollow needle extends into the container. The inhaler includes an aerosol generator that includes a vibratable membrane that aerosolizes liquid medication ejected from a cartridge for inhalation by a patient.

Description

Self-piercing liquid drug cartridges and associated dispensers

Cross References to Related Applications

This Patent Cooperation Treaty application claims priority to U.S. Patent Application No. 14/732,247, filed June 5, 2015; Priority, this application also claims priority to US Provisional Patent Application No. 62/099,806, filed January 5, 2015, which is incorporated herein by reference in its entirety for all purposes.

Background technique

Various types of inhalers exist for nebulizing liquids. For example, U.S. Patent No. 5,586,550 (the contents of which are incorporated herein by reference) describes an inhaler comprising a dispensing device in which a membrane having a tapered hole is vibrated to displace liquid in contact with the backside of the membrane. Dispensed as an aerosol from the front of the film.

While effective at aerosolizing liquids, such inhalers may not be particularly suitable for certain uses, such as nebulizing unit doses of insulin for pulmonary administration. Furthermore, such inhalers can employ less than ideal methods with regard to liquid delivery to the dispensing device, dose control, and microbial control.

Accordingly, improved methods of aerosolizing doses of insulin for pulmonary administration, liquid drug delivery to a dispensing device, dose control between doses, and/or microbial control are desirable.

Contents of the invention

The present invention provides liquid medicine cartridges and associated inhalers. In many embodiments, the cartridge includes a liquid drug container and a cartridge. The filter element is used to filter the liquid medicine in the container before spraying from the injection port of the container. The cartridge includes a piston that moves relative to the container to eject a volume of liquid from the container through the ejection port. In many embodiments, the liquid drug cartridge and associated inhaler are particularly suitable for aerosolizing doses of insulin for pulmonary administration. Liquid medication cartridges provide a convenient method of providing liquid medication to the aerosol generator. In many embodiments, the combination of the cartridge and the associated inhaler provides improved dosing control for administration and improved microbial growth inhibition between administrations.

Thus, in one aspect, a liquid medication cartridge is provided. The cartridge includes a container for storing a liquid medication, an end cap coupled to a first end of the container, a cartridge, and a plunger. The end cap has an ejection port through which a volume of liquid medicament can be selectively ejected from the container. The filter element is used to filter the liquid medicine before being ejected from the ejection port. A piston seals the second end of the container. The piston is repositionable relative to the container to selectively eject a volume of liquid medicament from the container through the ejection port.

The liquid drug cartridge may include additional elements and/or structures. For example, the end cap may have a protrusion in which the injection port is disposed. The cartridge may include a removable cover configured to interface with the end cap to prevent flow of liquid medication through the ejection port. The end cap may include a conduit in fluid communication with the jet port to deliver liquid medication to the jet port. The conduit can be coated to prevent microorganisms from entering the container. For example, the conduit may be coated with or made of silver to prevent microorganisms from entering the container.

The liquid drug cartridge may be configured to prevent any amount of liquid drug from escaping from the container without repositioning the piston relative to the container. For example, the conduit may be configured to prevent any amount of liquid drug from escaping from the container without repositioning the piston relative to the container. For example, to prevent gravity-induced flow of liquid drug from the cartridge without movement of the piston, the catheter may have an inner diameter that is sufficiently small relative to the surface tension and/or viscosity of the liquid drug to prevent the liquid drug from passing through the catheter. flow. The filter may also be configured to prevent any amount of liquid medicament from escaping from the container without repositioning the piston relative to the container.

Liquid drug cartridges may be configured to prevent microorganisms from entering the container. For example, the catheter can be coated (eg, with silver) to prevent microorganisms from entering the container. The filter element can also be configured to prevent microorganisms from entering the container. For example, the filter element may contain one or more antimicrobial substances and/or compounds (eg, silver).

In another aspect, an atomization system is provided. The system may include any of the liquid drug cartridge embodiments described herein, an aerosol generator including a vibratable membrane having a front and a back, a housing defining a mouthpiece, and a device for repositioning the piston relative to the container. An actuator positioned to dispense a dose of drug via the ejection port to the back of the vibratable membrane. The aerosol generator includes a vibratable element for vibrating the vibratable membrane. The housing includes a receptacle configured to at least partially receive the cartridge and engage with the cartridge to position the jet for dispensing the liquid drug directly onto the back of the vibratable membrane so as to be controlled by the vibratable element Vibration and atomization.

The system can be configured such that the liquid drug cartridge can be removed at any time to allow more thorough cleaning of the dispenser. When the liquid medicine cartridge is equipped with a detachable cover, the cover and the liquid medicine cartridge receiving the receptacle may be configured such that the liquid medicine cartridge cannot be inserted into the receptacle until the cover is detached from the case.

In many embodiments, the housing is configured to provide a mixture of air and aerosolized liquid medication for inhalation by the user. For example, the housing may include a mixing chamber in fluid communication with the front face of the vibratable membrane and the mouthpiece, and one or more valves in fluid communication with the mixing chamber and configured to introduce air into the mixing chamber in response to user inhalation through the mouthpiece. air inlet. The system may also include an array of air flow restrictors having a greater resistance to air flow than the one or more air inlets and placing the mixing chamber in fluid communication with the one or more air inlets. In many embodiments, the restrictor array includes a plurality of orifices arranged in an annular arrangement. In many embodiments, the air flow through the mixing chamber in response to the user's inhalation through the mouthpiece is laminar and surrounds a dose of medicament that is aerosolized using the vibratable membrane, thereby preventing contact of the aerosolized medicament with the mixing chamber. Contact between surrounding surfaces. The system may include a pressure port connected to a pressure sensing system for detecting inhalation by the patient.

A vibratable mesh can be coupled to the housing to increase the efficiency of the aerosol generator. For example, the vibratable mesh may be coupled to the housing via suitable isolator members, such as elastomeric isolators.

The system may include an ultraviolet light source to provide microbial control between doses. For example, one or more ultraviolet light sources may be used to irradiate a chamber of the housing disposed between the back of the vibratable member and the cartridge into which the drug is ejected from the liquid drug cartridge via the ejection port.

In many embodiments, the housing is configured to retain the liquid drug cartridge within the receptacle. Any suitable method may be used to retain the liquid drug cartridge inside the receptacle. For example, the housing may be configured to form a pressurizable container containing a liquid drug cartridge. The actuator may be configured to apply pressure to the container to reposition the piston relative to the container to dispense a dose of medicament via the ejection port to the back of the membrane. Injection of air into the container can be controlled to dispense a predetermined desired amount of liquid medicament via the jet for nebulization by the aerosol generator. For example, the piston may be positioned slightly below the end of the container, thereby creating a space that can be pressurized by sealing against the end of the container or the inner wall of the container. As another example, the side of the piston opposite the liquid drug can be hollowed out to create a pressurizable space. This pressurized space will increase when liquid is dispensed. Removal of air pressure (bleeding) can be used to immediately stop further movement of the piston until air pressure is reapplied.

In many embodiments, the actuator mechanically displaces the piston relative to the container to dispense a predetermined desired amount of liquid medicament via the ejection port for aerosolization by the aerosol generator. The actuator may include an adjustable metering mechanism operable to allow only a selectable amount of repositioning of the piston relative to the container for dispensing a selectable dose of the liquid drug.

In many embodiments, the misting system includes a control system for controlling various aspects of the misting system. For example, the control system may include one or more processors and tangible memory storing non-transitory instructions that, when executed by the one or more processors, cause the one or more processors to control the actuators to perform A priming cycle in which the actuator repositions the piston relative to the container until a drop has been ejected from the ejection orifice. The instructions may be operable to cause the one or more processors to determine that a droplet has been ejected from the ejection orifice by detecting when the vibratable member has been wetted by a droplet of ejected liquid medicament.

A self-piercing liquid drug cartridge and associated inhaler are also provided. In many embodiments, a liquid drug cartridge includes a liquid drug container and a needle assembly coupled to the container. When the liquid medicine cartridge is inserted into the associated inhaler, the hollow needle of the needle assembly pierces the liquid medicine cartridge, thereby forming a fluid passage by which the liquid medicine inside the container can be ejected to be atomized by the inhaler. In many embodiments, the liquid drug cartridge and associated inhaler are particularly suitable for aerosolizing doses of insulin for pulmonary administration. The self-piercing liquid medication cartridge provides a convenient method of providing liquid medication to an aerosol generator. In many embodiments, the combination of a liquid drug cartridge and an associated inhaler provides improved dosing control of administration and improved microbial growth inhibition between administrations.

Accordingly, in one aspect, a self-piercing liquid drug cartridge is provided. The liquid drug cartridge includes a container for storing a liquid drug, a septum configured to seal a first end of the container, a needle assembly coupled to the first end of the container, and a plunger to seal a second end of the container. The needle assembly includes a hollow needle and is repositionable between a first configuration in which the hollow needle does not extend through the septum and a second configuration in which the hollow needle extends through the septum. The piston is repositionable relative to the container to selectively eject a volume of liquid drug from the container through the hollow needle.

In many embodiments, the needle assembly includes a cap configured to couple the needle assembly with the container. For example, the lid may include a receiving groove shaped to receive and retain the end of the container (eg, with complementary shaped surfaces that provide a snap connection between the lid and the container end). In many embodiments, the cover includes an aperture configured to accommodate a portion of the hollow needle and movement of the hollow needle during resetting of the needle assembly from the first configuration to the second configuration. In many embodiments, there is an elastomeric seal disposed between the lid and the end of the container. The elastomeric seal prevents the escape of liquid from the container and the ingress of microorganisms and other contaminants.

In many embodiments, the needle assembly includes a guide element. The guide element may be configured to support the hollow needle in a fixed position and orientation relative to the guide element. The guide element may be configured to guide movement of the hollow needle relative to the container during resetting of the needle assembly from the first configuration to the second configuration. The guide element may include a receiving groove for receiving and engaging at least one of the cap and a portion of the container to limit relative movement between the container and the guide element to parallel to the direction of the hollow needle. panning. In many embodiments, the end of the hollow needle from which the liquid drug is ejected protrudes a predetermined controlled distance from the end face of the guide element.

In many embodiments, the needle assembly includes a spring element for biasing the needle assembly in the first configuration without displacement of the container relative to the guide element. For example, the needle assembly may include a coil spring disposed inside the guide element receiving groove and between an end wall of the guide element receiving groove and the needle assembly cover. Without causing displacement of the container and cap relative to the receiving groove of the guide element, the spring is in the undeformed configuration and the needle assembly is in the first configuration in which the hollow needle does not extend past the septum. By further displacing the container and cap into the receiving groove of the guide element, the spring can be compressed sufficiently to reset the needle assembly into a second configuration in which the hollow needle extends through the septum, thereby providing a means for dispensing the liquid drug in the container. A fluid pathway for ejection from a liquid drug cartridge through a hollow needle.

In many embodiments, the guide element includes structure to prevent the spring from pushing the guide element away from the cover. For example, the guide element may comprise a protruding formation on the inner surface of the guide element which slides in a groove on the outer surface of the cover. The slot may further be configured in the shape of a capital letter "L" to lock it in the first configuration for shipping. The patient will be required to twist the guide element before use to unlock it and allow the protrusion to slide in the axial direction of the cap. Alternatively, both ends of the spring may be mechanically fixed to the guide element and cover to provide retention between these parts. In many embodiments, the spring maintains a constant and specific distance between the outlet of the needle and the backside of the aerosol generating mesh, preventing contact between the needle and the mesh but still tight enough to transfer droplets onto the mesh .

In many embodiments, the hollow needle is coated to prevent microorganisms from entering the hollow needle and the container. For example, the needle can be coated with silver to inhibit microbial growth and/or entry. As another example, a self-piercing liquid drug cartridge may include a filter configured to inhibit the entry of microorganisms into the container.

In another aspect, an atomization system is provided. The nebulization system may include any of the self-piercing liquid drug cartridge embodiments described herein, a housing defining a mouthpiece, an aerosol generator disposed in the housing, and a liquid drug cartridge piston configured to move relative to the The container is repositioned to dispense a dose of liquid drug via the hollow needle to the actuator of the aerosol generator. The housing includes a receptacle configured to at least partially receive the cartridge and engage the needle assembly to reset the needle assembly from the first configuration to the second configuration during insertion of the cartridge into the receptacle. The aerosol generator includes a vibratable membrane having a front and a back, and a vibratable element for vibrating the membrane. The actuator is configured to reposition the piston relative to the container to dispense a dose of drug via the hollow needle to the back of the vibratable membrane. The system can be configured such that the liquid drug cartridge can be removed at any time to enable more thorough cleaning of the dispenser. When the liquid medicine cartridge is equipped with a detachable cover, the cover and the receptacle for receiving the liquid medicine cartridge may be configured such that the liquid medicine cartridge cannot be inserted into the receptacle until the cover is detached from the liquid medicine cartridge.

In many embodiments, the housing is configured to provide a mixture of air and aerosolized liquid medicament for inhalation by the user. For example, the housing may include a mixing chamber in fluid communication with the front face of the vibratable membrane and the mouthpiece, and one or more valves in fluid communication with the mixing chamber and configured to introduce air into the mixing chamber in response to user inhalation through the mouthpiece. air inlets. The system may also include an array of air flow restrictors having a greater resistance to air flow than the one or more air inlets and placing the mixing chamber in fluid communication with the one or more air inlets. In many embodiments, the restrictor array includes a plurality of orifices arranged in an annular arrangement. In many embodiments, air flowing through the mixing chamber in response to user inhalation through the mouthpiece is laminar and surrounds a dose of medicament aerosolized using the vibratable membrane, thereby preventing the aerosolized medicament from interfering with the surroundings of the mixing chamber. contact between surfaces. The system may include a pressure port connected to a pressure-sensing sensing system for detecting patient inhalation.

A vibratable mesh can be coupled to the housing to increase the efficiency of the aerosol generator. For example, the vibratable mesh may be coupled to the housing via suitable isolator members, such as elastomeric isolators.

The system can include an ultraviolet light source to provide microbial control between doses. For example, one or more ultraviolet light sources may be used to irradiate a chamber in the housing disposed between the back of the vibratable member and the cartridge and into which drug is ejected from the liquid drug cartridge via the hollow needle.

In many embodiments, the housing is configured to retain the liquid drug cartridge within the receptacle. The liquid drug cartridge may be retained within the receptacle by any suitable method. For example, the housing may be configured to form a pressurizable container containing a liquid drug cartridge. The actuator may be configured to apply pressure to the container to reposition the piston relative to the container to dispense a dose of drug via the hollow needle to the back of the membrane. The injection of air into the container can be controlled so that a predetermined desired amount of liquid drug is dispensed through the hollow needle for nebulization by the aerosol generator. For example, the piston may be positioned slightly below the end of the container, thereby creating a pressurizable space by sealing against and abutting the end of the container or the inner wall of the container. As another example, the piston can be hollowed out on the side opposite the liquid drug, creating a space that can be pressurized. This pressurized space will increase when liquid is dispensed. Removal of air pressure (venting) can be used to immediately stop further movement of the piston until air pressure is reapplied.

In many embodiments, the actuator mechanically displaces the piston relative to the container to dispense a predetermined desired amount of liquid drug via the hollow needle for aerosolization by the aerosol generator. The actuator may include an adjustable metering mechanism operable to allow only a selectable amount of repositioning of the piston relative to the container for dispensing a selectable dose of the liquid drug.

In many embodiments, the misting system includes a control system configured to control various aspects of the system. For example, the control system may include one or more processors and tangible memory storing non-transitory instructions that, when executed by the one or more processors, cause the one or more processors to control the actuators to complete a start cycle, where the actuator repositions the piston relative to the container until the droplet has been ejected from the hollow needle. The instructions may be used to cause the one or more processors to determine that a droplet has been ejected from the hollow needle by detecting when the vibratable member has been wetted by an ejected droplet of liquid drug.

Description of drawings

Figure 1 is a cross-sectional view of a liquid drug cartridge, according to many embodiments.

2 is a cross-sectional view illustrating an inhaler into which a drug cartridge may be inserted, according to many embodiments.

3 is a diagram illustrating the drug cartridge of FIG. 1 inserted into the inhaler of FIG. 2 and held by an end member, and liquid drug ejected from the liquid drug cartridge being aerosolized for use by a user, according to many embodiments. Cutaway view of the inhalation.

4 is an end view illustrating the flow restricting orifice array of the inhaler of FIG. 2, according to many embodiments.

5 is a simplified schematic diagram illustrating components of an inhaler for receiving liquid medication from a medication cartridge, according to many embodiments.

6 is a cross-sectional view of another liquid drug cartridge, according to many embodiments.

7 is a cross-sectional view of a liquid drug cartridge including a one-way valve, according to many embodiments.

8 is a cross-sectional view illustrating the drug cartridge of FIG. 7 inserted into the inhaler of FIG. 2 , and liquid drug ejected from the cartridge being aerosolized for inhalation by a user, according to many embodiments.

9 is a partial cutaway side view of a self-piercing liquid drug cartridge, according to many embodiments.

10 is a partial cross-sectional side view of a removable cover coupled to an end of the drug cassette of FIG. 9, according to many embodiments.

11 is a side view illustrating the drug cartridge of FIG. 9 partially inserted into the inhaler of FIG. 2, according to many embodiments.

12 is a side view illustrating the drug cartridge of FIG. 9 inserted into the inhaler of FIG. 2 into the inhaler to a depth sufficient to cause the hollow needle to penetrate through the septum to form a Fluid pathway that ejects liquid medication from the cartridge.

13 is a diagram illustrating the drug cartridge of FIG. 9 fully inserted into the inhaler of FIG. 2 and retained by an end member, and liquid drug ejected from the cartridge being aerosolized for inhalation by a user, according to many embodiments side view.

14 is a side view of another self-piercing liquid drug cartridge partially inserted into the inhaler of FIG. 2, according to many embodiments.

15 is a side view illustrating the self-piercing liquid drug cartridge of FIG. 14 inserted into the inhaler of FIG. 2 far enough to cause the hollow needle to penetrate through the septum and into the filter, according to many embodiments. depth thereby forming a fluid pathway for ejecting liquid medicament from the cartridge.

detailed description

Liquid drug cartridges and associated inhalers are described herein. In many embodiments, a liquid drug cartridge containing a drug formulation is inserted into the dispenser until the cartridge contacts a protruding stop of the dispenser. In many embodiments, serial dispensing of pharmaceutical formulations and dispensing of very small and very large doses from the same cassette is possible.

The liquid drug cartridge can be biased into contact with the mating surface of the inhaler to ensure precise and tight positioning of the ejection opening relative to the vibratable membrane of the inhaler such that surface tension will cause liquid drug droplets to The drops will attach to the vibratable membrane even when the inhaler is oriented horizontally. The attachment is controlled by the distance between the jet and the vibratable membrane, the inner diameter of the jet, and the geometry of the jet in which the droplet resides.

The membrane vibrates to generate the aerosol and causes a pumping action, thereby pulling the droplet out of the ejection orifice and through the membrane. At the end of the dose, there are no residual droplets to be nebulized due to the pumping action of the membrane. In many embodiments, the vibratable membrane is coupled to the housing of the inhaler using elastic vibration isolators to maximize the efficiency of aerosol generation.

In many embodiments, when the patient inhales, air flows through the air inlet into the shunt and then through the restrictor array. This flow of air delivers the aerosol to the patient. In many embodiments, the air inlet has significantly less resistance than the restrictor array. A pressure port and associated pressure sensor may be included to detect the intensity of the patient's inhalation.

The liquid drug cartridge may be configured to prevent microorganisms from entering the liquid drug container. For example, an end cap may include a conduit that is coated (eg, with silver) to prevent microorganisms from entering the conduit and liquid drug container. In many embodiments, after a dose is dispensed, there is no reverse flow back into the container (ie, any drug in the catheter comes into contact with the antimicrobial coating to inhibit the proliferation of pathogenic bacteria). The liquid drug cartridge may include a filter configured to prevent microorganisms from entering the container.

The liquid drug cartridge is configured to protect the user from accidental needle sticks. For example, the injection port could be integrally formed into the end cap, thereby avoiding the use of a needle. A removable protective cap can be used to protect the jet port from damage and contamination. The protective cover may be shaped such that the liquid drug cartridge cannot be inserted into the inhaler until the protective cover is removed.

The liquid drug cartridge includes a piston slidably disposed inside the container for dispensing the liquid drug without the introduction of air. This feature improves the physical stability of the drug product, supports the use of the liquid drug cartridge in a horizontal orientation, and maintains the container in a sealed configuration at all times for consistent dosing.

Any suitable method for actuating the piston may be employed. For example, the piston may be air driven by adding a seal between the end member and the housing of the inhaler, or the piston may be driven mechanically with an actuation mechanism coupled to or past the end member.

A pre-fill cycle may be used to inject air from the container and/or the injection port. For example, after loading a liquid drug cartridge into an associated inhaler, a mechanical plunger may be brought into contact with the piston and pushed until a droplet of formulation is dispensed. This can be sensed by the aerosol generator software which can be used to detect the difference between a wet vibratable membrane and a dry vibratable membrane.

The inhaler may include additional microbial control features. For example, a violet light can be added to the chamber in which droplets are ejected from the jet orifice, providing additional microbial control between doses.

The liquid medicine cartridge and the inhaler may be configured such that the liquid medicine cartridge can be removed and inserted at any time. For example, the liquid drug cartridge can be removed at any time to improve accessibility for cleaning the inhaler. In many embodiments, reinsertion of the liquid drug cartridge results in a priming cycle.

In many embodiments, the inhaler includes: a housing defining a dispensing outlet, a vibratable membrane having a front exposed at the outlet and a back for receiving dispensed liquid, and a vibratable membrane connected to the housing and operable to vibrate the membrane. Vibrating mechanism thereby dispensing an aerosol of liquid through the membrane. A liquid delivery system is used to deliver metered amounts of liquid to the back of the membrane. In this way, a metered amount of liquid may be dispensed at the outlet by operating the vibrating mechanism for a period of operation sufficient to completely atomize the metered amount of liquid delivered to the back of the vibratable member.

An advantage of this device is that it facilitates dispensing in a single dose substantially all of the liquid in contact with the back of the membrane, especially when the volume of the metered dose is relatively small. By dispensing the entire dose, the membrane is substantially free of fluid from one dose to the next. In this way, contact between the liquid and the surrounding air can thereby be avoided during periods of non-use between successive uses. This is especially important for pharmaceutical formulations as this eliminates the need to use preservatives in the liquid and avoids evaporation losses. For example, various preservative-free insulin formulations that may be used include US Patent Application No. 13/004,662 entitled "Preservative-Free Insulin Formulations and Systems and Methods for Nebulization" and US Patent Application No. 13/004,662 entitled "Liquid Insulin Formulations". As described in Provisional Patent Application No. 62/120,573, the entire contents of each patent application are incorporated herein by reference.

Such devices are particularly useful for the administration of inhaled pharmaceutical liquid products requiring entrainment of a fine aerosol of the liquid in the flow of inspiratory air through the mouthpiece. An example of such a liquid is an insulin composition.

In many embodiments, the liquid drug cartridge is a multi-dose cartridge. For example, a liquid drug cartridge may contain enough drug for 1 day, 1 week, or 1 month of treatment. The volume of the dose dispensed from the liquid drug cartridge may be controlled by any suitable method, such as by positioning of the piston. The movement position of the piston can be set by an external controller. For example, the piston may be moved in small enough increments to eject very small volumes of liquid (eg, 10 μL of liquid) or large volumes of liquid (eg, 1000 μL of liquid), thereby delivering small or large amounts of drug. The position of the plunger can be maintained in a fixed position after a dose until a future dose is required. For dispensing subsequent doses, the piston can be moved past the latter position to deliver further doses until the drug cartridge is empty.

Turning now to the drawings, wherein like reference numerals refer to like parts. Figure 1 illustrates a liquid drug cartridge 10, according to many embodiments. The liquid drug cartridge 10 includes a container assembly 12 , an end cap assembly 14 , and a filter 16 .

Container assembly 12 is configured to store liquid medication for subsequent dispensing into the inhaler. The container assembly 12 includes a container 18 having openings at opposite ends of the container 18 . End cap assembly 14 seals a first end of container 18 . The piston 20 seals the second end of the container 18. Piston 20 is selectively slidable within container 18 to eject a selected amount of liquid medication from container 18 .

The end cap assembly 14 has an ejection port 22 from which liquid medication is ejected. In many embodiments, the end cap assembly 14 is configured such that the injection port 22 is located at the end of the protrusion of the end cap assembly 14 so as to be in a precise position relative to the mating surface 24 of the end cap assembly 14 .

The end cap assembly 14 includes an end cap body 26 , a conduit 28 , and a removable cap 30 . Lid 30 may be used to provide a microbial barrier prior to the first use of the cartridge. This microbial barrier can be achieved by sealing and abutting the end cap assembly 14, or by incorporating the cap 30 with the cap assembly 14 into a unitary body that separates when the cap is removed. The end cap body 26 may be made of a suitable material (eg, a suitable resilient material) and shaped to interface with a complementary shaped end of the container 18 . In the illustrated embodiment, conduit 28 is a cylindrical metal member having a suitable inner diameter. For example, the inner diameter of conduit 28 may be selected to be large enough to allow controlled flow of liquid drug when the piston is controllably displaced relative to container 18, but small enough to allow for controlled flow of liquid drug without movement of piston 20 relative to container 18. prevent the flow of liquid medication.

The filter 16 is used to filter the liquid medicine sprayed from the container 18 before passing through the conduit 28 . In the illustrated embodiment, the filter 16 has a cylindrical body made of a suitable filter material. For example, a sintered polyethylene filter with a 0.2 to 100 μm pore size, or a membrane made of nylon, PTFE, polypropylene or other material compatible with the liquid drug 10 . This filter can be designed similar to a syringe filter. Flow of liquid medicament in the container through the filter 16 is induced by controlled movement of the piston 20 relative to the container 18 . After passing through the filter 16 , the liquid drug is expelled through the conduit 28 and through the injection port 22 . Filter 16 may be configured to prevent liquid medication from flowing into conduit 28 without movement of the piston relative to container 18 .

Figure 2 illustrates a cross-sectional view of an inhaler 40 configured for use with a drug cartridge 10, according to many embodiments. The inhaler 40 includes a housing 42 and an aerosol generator 44 fitted to the housing 42 via a vibration isolator 46 . The housing 42 defines a receptacle 48 configured to slidably receive the drug cartridge 10 . The inner surface 50 of the receptacle 48 is configured to abut the outer surface of the cartridge 10 such that the drug cartridge 10 is constrained to slideably translate relative to the receptacle 48 . The abutment surface 24 of the end cap assembly 14 contacts the protruding stop 52 of the inhaler 40 , thereby positioning the spray opening 22 in a fixed position relative to the aerosol generator 44 .

The aerosol generator 44 comprises a vibratable membrane having a front face 54 exposed to the outlet channel 56 and a back face 58 in contact with liquid ejected from the cartridge 10 in use. Aerosol generator 44 is mounted to housing 42 via vibration isolator 46 and is operable to dispense the active medicament in aerosol form through mouthpiece 60 .可以使用的示例性气雾剂发生器也描述于美国专利5164740、6629646、6926208、7108197、5938117、6540153、6540154、7040549、6921020、7083112、7628339、5586550、5758637、6085740、6467476、6640804、7174888、6014970 , 6205999, 6755189, 6427682, 6814071, 7066398, 6978941, 7100600, 7032590, 7195011, the contents of these patents are incorporated herein by reference. These references describe exemplary aerosol generators, methods of making such aerosol generators, and methods of providing liquids to aerosol generators, and are incorporated herein by reference for at least these feature. The aerosol generator may comprise a vibratable membrane having a conical aperture with a dimension in the range of about 3 meters to about 8 meters, preferably about 3 meters to about 6 meters, in some cases is about 4 meters. The membrane may have a dome shape and be vibrated with an annular piezoelectric element circumscribing the hole. The diameter of the membrane may range from about 5mm to about 8mm. The film may also have a thickness in the range of about 50 microns to about 70 microns. Typically, the membrane will vibrate at a frequency in the range of about 50 kHz to about 150 kHz.

FIG. 3 shows the drug cartridge 10 installed in the inhaler 40 . The end member 66 retains the drug cartridge 10 to maintain contact between the docking surface 24 of the end cap assembly 14 and the protruding stop 52 of the inhaler 40, thereby precisely controlling the position of the ejection port 22 relative to the back surface 58 of the vibratable membrane. .

Inhaler 40 may include a suitable actuator for displacing piston 20 relative to container 18 to eject a desired preselected dose of liquid medicament from container 18 via ejection port 22 . For example, end member 66 and housing 42 may form a pressurizable reservoir into which air may be injected to displace piston 20 toward injection port 22 . As another example, the piston 20 may be controllably displaced toward the injection port 22 using an actuation mechanism coupled to or acting through the end member 66 .

In use, a user inhales from the mouthpiece 60 and the aerosol generator 44 simultaneously aerosolizes a dose of liquid medicament ejected from the ejection port 22 by corresponding actuation of the piston 20 . Housing 42 includes one or more air inlets 68 and a restrictor array 70 by which air is directed into mixing chamber 72 for mixing with the aerosolized liquid drug dose prior to inhalation by the user.

FIG. 4 shows an end view of a restrictor array 70 including an annular arrangement of orifices 74 . The size of the orifice 74 is designed such that the user inhales for a sufficient period of time to properly aerosolize the liquid drug dose. In many embodiments, one or more air inlets 68 have significantly less resistance to air flow than restrictor array 70 . In many embodiments, restrictor array 70 is configured to create a laminar air flow surrounding the formed flow of aerosolized liquid drug, thereby preventing or even substantially preventing contact between the aerosolized drug and mixing chamber 72 surfaces.

In many embodiments, the inhaler 40 includes an ultraviolet light source for illuminating at least a portion of the chamber 76 into which the ejection end of the hollow needle 16 ejects liquid medication. The UV light source can be used to provide enhanced microbial control, for example, in the period between administrations.

In many embodiments, the inhaler 40 includes a pressure port 78 that is coupled to a pressure sensing system to detect inhalation by the patient. For example, a pressure sensor can be used to determine when the patient starts breathing to activate the aerosol generator, and when the patient stops breathing to stop aerosol generation to prevent waste, maximize dose efficiency, and maintain constant delivery.

FIG. 5 shows a simplified schematic diagram of the components of the inhaler 40 . Inhaler 40 includes control electronics 80, input/output device 82, aerosol generator 44, inhalation intensity monitoring system 84, ultraviolet light source 86, piston actuation system 88, one or more batteries 90, and/or an external port 92. Control electronics 80 are operatively connected to input/output device 82, aerosol generator 44, inhalation intensity monitoring system 84, ultraviolet light source 86, piston actuation system 88, one or more batteries 90, and/or external port 92 connect.

Any suitable configuration of control electronics 80 may be employed. For example, in the illustrated embodiment, control electronics 80 includes one or more processors 94 and tangible memory 96 . Memory 96 may include read only memory (ROM) 98 and/or random access memory (RAM) 100 . Memory 96 stores instructions that, when executed by one or more processors 94 , cause the processors to control the operation of the various subsystems of inhaler 40 .

For example, these instructions may be used to cause the control electronics 80 to receive input from the user via the input/output device 82 regarding the desired dose of liquid medicament dispensed by the inhaler 40 . The control electronics 80 may receive a signal from an inhalation intensity monitoring system 84 that is indicative of inhalation by the user via the inhaler 40 . In response to a signal indicative of user inhalation, the control electronics may cause the actuation system 88 to spray a dose of liquid medication to the aerosol generator 44 and cause the aerosol generator 44 to activate the The sprayed dose is atomized. The control electronics may be configured to discontinue aerosol generation in response to a signal indicating when the patient ceases inhalation.

Any suitably configured input/output device 82 may be used. For example, input/output device 82 may include input keys and a display device (eg, an LCD screen and/or one or more indicator lights).

Inhalation monitoring system 84 may include a pressure sensor operatively coupled to pressure port 78 . The pressure sensor outputs a signal indicative of the pressure at pressure port 78 to control electronics 80 . Control electronics 80 may be used to monitor the pressure signal from the pressure sensor to detect a decrease in pressure associated with the flow of air through the inhaler due to inhalation by the user.

The ultraviolet light source 86 can be energized periodically for any suitable length of time to provide microbial control between doses. The UV light source can be selected to provide a spectrum of appropriate wavelengths to kill microorganisms. For example, control electronics 80 may be configured to energize UV light source 86 according to a predetermined schedule following administration of any particular dose.

One or more batteries 90 may be connected to the various subsystems of the inhaler in any suitable manner. For example, one or more batteries 90 are directly wired to any particular subsystem with control electronics 80 to control the associated switches for controlling the supply of power from one or more batteries 90 to that particular subsystem. One or more batteries 90 may be replaceable and/or rechargeable.

In embodiments where one or more batteries 90 are rechargeable, recharging may be accomplished via external port 92 . External port 92 may also be used to transmit data to and/or from control electronics 80, such as program instructions, and/or operating parameters for operational control of inhaler 40, and/or to be Inhaler usage data exported to external systems for review and/or analysis.

The inhaler 40 may be operated to deliver a metered amount of liquid medication from the cartridge 10 to the back 58 of the vibratable membrane 64 . Thus, for each use, a metered amount of aerosolized medicament may be dispensed at the mouthpiece 60 outlet by operation of the aerosol generator 44 .

Cassette 10 contains a reservoir of active medicament from which a predetermined dose of medicament can be dispensed. For example, insulin in a dose of between about 80 to about 120 microliters. The lower limit is usually at least about 15 microliters, and the upper limit is usually about 1,000 microliters to about 2,000 microliters. A particularly useful range is about 80 microliters to about 120 microliters at a concentration of about 100 insulin units/ml or greater, more preferably between about 200-800 units/ml, and in some cases up to 2,500 units /ml.

Conduit 28 provides fluid passage for liquid medication to vibratable membrane 64 . Injection port 22 is located very close to rear face 58 of diaphragm 64 . Typically, the injection port 22 will be located less than 5 mm, more preferably less than 2 mm, from the rear face 58 . Conduit 28 may be fabricated from, for example, type 316 stainless steel alloy having gage dimensions in the range of 22 gage to 26 gage.

When the cartridge 10 is installed in the inhaler 40, the indicator light may begin to flash to signal the patient that the inhaler 10 is ready for use. At any time thereafter, the patient can inhale through the mouthpiece 60 . Patient inhalation is detected by a flow sensor. Detection of patient inhalation causes activation of aerosol generator 44 to generate aerosol particles that enter mixing chamber 56 . The aerosol is entrained in the inhaled air flow and flows through the respiratory system to the patient's lungs. When the full dose has been nebulized (one or more breaths may be taken), the "end of dose" indicator light may illuminate a second time to inform the patient that the full dose has been delivered. Full dose delivery is achieved when at least about 95%, more preferably 98%, and most preferably greater than 99% of the dose is delivered. To receive the dose, the patient may take several inhalations or a single inhalation based on the volume of liquid drug delivered to the diaphragm 64 and the patient's vital capacity. Each inhalation should be a deep breath to ensure that the aerosol reaches the deep parts of the lungs.

The inhaler may be configured to accommodate cleaning and/or sterilization of the vibratable membrane and/or chamber into which the cartridge 10 injects liquid medication. The inhaler may include a vent and/or drain structure so that a cleaning fluid (eg, water or any suitable fluid) may be introduced or exhausted into or out of the chamber into which the cartridge 10 injects liquid medication. Control electronics may be sealed in one or more separate chambers from contact with cleaning fluid. A cleaning cartridge containing a cleaning fluid (eg water or any suitable fluid) may occasionally be installed for cleaning the mesh. If a person tries to inhale water vapor, the pressure sensor can be reversed to shut the inhaler off. There may be a "soak" mode in which water droplets are allowed to sit on the web with occasional vibrations, eg to provide alternating soak, rinse, soak, rinse cycles. A simpler construction would employ a plastic funnel with a small opening at the top so that the patient would insert the plastic funnel into the cartridge slot and drip water into the inhaler. This small opening can be used to limit the amount of water to a slow drip.

FIG. 6 illustrates another liquid drug cartridge 110 that may be used with an inhaler (eg, inhaler 40 ), according to many embodiments. The drug cartridge 110 includes a container 112 , a filter 16 , an end cap 114 , and a removable cap 116 . The end cap 114 has a protrusion 118 that provides a fluid conduit 120 and injection port 22 through which liquid medication is injected onto the back surface 58 of the vibratable membrane 64 . As with fluid conduit 28, the inner diameter of conduit 120 can be selected to be: large enough to allow controlled flow of liquid medication when controllably displacing piston 20 relative to container 112, but still small enough to allow the controlled flow of liquid medication when piston 20 is not opposed The flow of liquid medication is prevented in the event of container 112 movement. The inside of conduit 120 may be coated (eg, with silver) to inhibit entry of microorganisms into cassette 110 .

FIG. 7 illustrates another liquid drug cartridge 210 in accordance with many embodiments. The drug cassette 210 is similar in construction to the drug cassette 10 but includes a one-way valve 212 in addition to the container assembly 12 and end cap assembly 14 described herein with respect to the drug cassette 10 . Although not included in the illustrated embodiment, liquid drug cartridge 210 may also include a filter element, such as that of drug cartridge 10 . For example, one or more filters the same as or similar to filter 16 may be positioned upstream of one-way valve 212 and/or downstream of one-way valve 212 .

In many embodiments, one-way valve 212 is used to provide a physical barrier that prevents microorganisms from entering the liquid medication stored inside container 18 . Any suitable configuration may be used for one-way valve 212 to ensure only one-way flow of liquid medication from container 18 to conduit 28 . For example, one-way valve 212 may be a duckbill valve or a mechanical valve, such as a spring-loaded ball valve. The opening and closing of the one-way valve 212 may be controlled by the pressure inside the container 18 due to the actuation of the piston 20, as described herein. One-way valve 212 may be mechanically and/or electrically actuated. Exemplary suitable one-way valve configurations that may be employed are described in US Patents 5,759,101 and 6,089,260, and US Patent Applications 2015/0048119 and 2012/0041381; the entire disclosures of these patent documents are incorporated herein by reference.

FIG. 8 shows the cartridge 210 installed into the inhaler 40 . The end member 66 holds the cartridge 210 to maintain contact between the abutment surface 24 of the end cap assembly 14 and the protruding stop 52 of the inhaler 40 , thereby precisely controlling the position of the jet opening 22 relative to the vibratable membrane face 58 .

As described herein, in many embodiments, the inhaler 40 is configured to controllably displace the piston 20 relative to the container 18 . The displacement of the piston 20 relative to the container 18 can be used to increase the internal pressure of the container 18 thereby opening the one-way valve 212, thereby ejecting a desired preselected dose of liquid medicine from the container 18 through the injection port 22 for inhalation by the user, as described in this article.

self-piercing liquid drug cartridge

Embodiments of self-piercing liquid drug cartridges are also described herein. In many embodiments, a self-piercing liquid drug cartridge containing a drug formulation is inserted into the dispenser until a guide element of the cartridge contacts a protruding stop of the dispenser. As the cartridge is inserted further into the dispenser, the liquid drug cartridge's cap and container assembly slides inside the guide element and abuts the sharp end of the drug cartridge's hollow needle. The hollow needle pierces the septum to form a fluid pathway for ejecting liquid medication from the container of the cartridge to be aerosolized by the inhaler for inhalation by the user. In many embodiments, serial dispensing of formulations, and dispensing of very small and very large doses from the same cartridge is possible.

The cartridge comprises a spring which ensures that the guide element remains in contact with the protruding stop and is retained by the end member of the inhaler after the cartridge has been fully inserted into the inhaler. The protruding stop provides precise and tight positioning of the hollow needle relative to the vibratable membrane of the inhaler, so when a drop of liquid drug is dispensed via the hollow needle, the surface tension causes the drop of drug to adhere to the vibratable membrane, even when inhaled. when the device is in the horizontal direction. The attachment is controlled by the distance between the hollow needle and the vibratable membrane, the inner diameter of the hollow needle, and the geometry of the hollow needle in which the droplet is present.

The membrane vibrates to generate the aerosol and causes a pumping action, thereby pulling the droplet away from the hollow needle and through the membrane. At the end of the dose, there are no remaining droplets to be nebulized due to the pumping action of the membrane. In many embodiments, elastomeric isolators are used to couple the vibratable membrane to the housing of the inhaler to maximize the efficiency of aerosol generation.

The hollow needles can be coated (for example with silver) to prevent microorganisms from entering the hollow needles and the liquid drug container. In many embodiments, after dispensing a dose, there is no reverse flow back into the container (ie, any drug in the needle remains therein in contact with the antimicrobial coating to inhibit the proliferation of pathogenic bacteria). The self-piercing liquid drug cartridge may include a filter configured to prevent microorganisms from entering the container.

The liquid drug cartridge is configured to protect the user from accidental needle sticks. Only one end of the hollow needle is pointed and the guide element supports and surrounds the hollow needle such that the pointed end of the hollow needle is not exposed and is oriented towards the septum. The exposed end of the hollow needle is not sharp. A removable protective cap protects the exposed end of the hollow needle from damage and contamination. The shape of the protective cap is designed such that the cartridge cannot be inserted into the inhaler until the protective cap is removed.

The drug cartridge includes a piston slidably disposed inside the container for dispensing liquid drug without introduction of air. This feature keeps the hollow needle submerged during dispensing, improves the physical stability of the drug product, supports the use of the liquid drug cartridge in a horizontal orientation, and maintains the container in a sealed configuration at all times for consistent dosing.

The drug cartridge and inhaler can be configured such that the liquid drug cartridge can be removed and reinserted at any time. For example, the liquid drug cartridge can be removed at any time to enhance access for cleaning the inhaler. In many embodiments, reinsertion of the liquid drug cartridge results in a prefill cycle. In such an embodiment, the septum may be configured to be pierced multiple times without affecting the sterility of the container.

Figure 9 illustrates a self-piercing liquid drug cartridge 310 in accordance with many embodiments. The liquid drug cartridge 310 includes a container assembly 312 and a needle assembly 314 coupled to the container assembly 312 and including a hollow needle 316 .

Container assembly 312 is used to store liquid medication for subsequent dispensing into the inhaler. The container assembly 312 includes a container 318 having openings at opposite ends of the container 318 , a septum 320 sealing the first end of the container 318 , and a piston 322 sealing the second end of the container 318 . The septum 320 is configured to be pierced by the hollow needle 316 to form a fluid pathway through which the liquid medicament inside the container 318 can be dispensed to the inhaler. Piston 322 is selectively slidable within container 318 to eject a selected amount of liquid medication from container 318 through hollow needle 316 .

Needle assembly 314 is resettable between a first configuration in which hollow needle 316 does not extend through septum 320 (shown in FIG. 9 ) and a second configuration in which hollow needle 316 extends through septum 320 (see, eg, FIG. 13 ). Needle assembly 314 includes hollow needle 316 , cap 324 , guide element 326 , and spring 328 . In the illustrated embodiment, cap 324 is configured to couple needle assembly 314 to container assembly 312 . Needle assembly 314 may be coupled to container assembly 312 in any suitable manner. For example, in the illustrated embodiment, the cover 324 is configured to receive the first end of the container assembly 312 and utilize a complementary snap-fit feature of the cover 324 and the container assembly 312 to retain the received portion. Guide member 326 includes a receiving slot 330 configured to slidably receive and interface lid 324 and a portion of container assembly 312 . The opposite ends of the spring 328 are respectively coupled with the end wall 332 of the receiving groove 330 and the cover 324 . In the first configuration, the spring 328 is in an unbiased configuration and maintains the illustrated separation between the cover 324 and the end wall 332 of the receiving slot 330 , thereby positioning the hollow needle 316 in a diagram relative to the septum 320 . location. The guide element 326 has an outer surface 334 and an outer end wall surface 336 .

FIG. 10 shows the removable protective cover 362 coupled with the cartridge 310 . The protective cap 362 protects the hollow needle 316 from damage and contamination. The shape of the cover 362 is designed to prevent insertion of the cartridge 310 into the inhaler 40 unless the cover 362 is removed.

FIG. 11 shows the cartridge 310 partially inserted into the inhaler 40 . Upon insertion of the cartridge 310 into the receptacle 48 , the cartridge 310 remains in the first configuration in which the hollow needle 316 does not extend past the septum 320 until the end wall outer surface 336 contacts the protruding stop 52 .

FIG. 12 shows the cartridge 310 almost completely inserted into the inhaler 40 . In the illustrated configuration, guide element 326 is in contact with protruding stop 52 and container assembly 312 has been urged toward guide element 326 , thereby partially compressing spring 328 and inserting the sharp end of hollow needle 316 through septum 320 . The force of the spring 328 keeps the guide element 326 in contact with the protruding stop 52 , thereby fixing the position of the injection end of the hollow needle 316 relative to the vibratable membrane 64 of the aerosol generator 44 .

FIG. 13 shows the cartridge 310 fully inserted into the inhaler 40 . End member 66 retains cartridge 310 and resists the force applied to container assembly 312 by compressed spring 328 . The compressed spring 328 maintains the guide element 326 in contact with the protruding stop 52 , thereby maintaining the preferred predetermined position of the injection end of the hollow needle 316 relative to the vibratable membrane 64 . Although the sharp end of the hollow needle 316 is illustrated in FIG. 13 as being located a significant distance beyond the inner wall of the septum 320, in many embodiments the sharp end of the hollow needle 316 is located closer to the septum 320 to increase the amount of fluid that can be removed from the septum 320. The amount of insulin dispensed in the drug cartridge.

Inhaler 40 may include a suitable actuator for displacing piston 322 relative to container 318 to eject a desired preselected dose of liquid medicament from container 318 through the ejection end of hollow needle 316 . For example, end member 66 and housing 42 may form a pressurizable container into which air may be injected to displace piston 322 toward guide element 326 . As another example, the piston 322 may be controllably displaced toward the guide element 326 using an actuation mechanism coupled to or acting through the end member 66 .

In use, a user inhales from mouthpiece 60 while aerosol generator 44 simultaneously aerosolizes a dose of liquid medicament expelled from the spray end of hollow needle 316 by corresponding actuation of piston 322 . Housing 42 includes one or more air inlets 68 and a restrictor array 70 through which air is directed into a mixing chamber 72 for mixing with an aerosolized dose of liquid medicament prior to inhalation by the user.

As an example, a self-piercing liquid drug cartridge may have a configuration similar to cartridge 310 shown in FIG. 9 , but without spring 328 . In this configuration, the cartridge can be configured in a first configuration in which the hollow needle 316 does not extend through the septum 320 (similar to the first configuration of the cartridge 310 shown in FIG. Reset between the second configuration (similar to the second configuration of the cartridge 310 shown in Figure 13). For example, the cartridge may include one or more locking features (eg, one or more engagement features of guide member 326 and cover 324 ) that maintain the liquid drug cartridge in the first configuration prior to installation into the inhaler. When the drug cartridge is installed into the inhaler, one or more locking structures may allow relative movement between the guide member 326 and the cover 326 in response to the compressive force generated by the installation, thereby resetting the liquid drug cartridge into the second configuration. In many embodiments without spring 328, the liquid drug cartridge is in the second configuration after being reset to the second configuration. In addition, one or more additional locking structures of the docking (eg, one or more docking structures of the guide member 326 and the cover 324 ) may be used to maintain the guide member 326 in contact with the protrusion when the drug cartridge is in the second configuration. The stop 52 contacts, thereby maintaining the preferred predetermined position of the injection end of the hollow needle 316 relative to the vibratable membrane 64 .

14 and 15 illustrate a self-piercing liquid drug cartridge 430 for the inhaler 40, according to many embodiments. Drug cartridge 430 includes container assembly 412 , filter 416 , septum 432 , and needle assembly 434 coupled to container assembly 412 and including hollow needle 436 .

Container assembly 412 is configured to store liquid medication for subsequent dispensing into the inhaler. Container assembly 412 includes container 418 having openings at opposite ends of container 418 , filter 416 , septum 432 sealing container 418 at a first end, and piston 420 sealing container 418 at a second end. The septum 432 is configured to be pierced by a hollow needle 436 to form a fluid pathway by which the liquid medicament inside the container 418 can be dispensed into the inhaler. Hollow needle 436 may partially pierce filter 416 such that liquid medication passes through at least a portion of filter 416 before entering hollow needle 436 . Piston 420 is selectively slidable within container 418 to eject a selected amount of liquid medication from container 418 via hollow needle 436 .

Needle assembly 434 is resettable between a first configuration in which hollow needle 436 does not extend through septum 432 (shown in FIG. 14 ) and a second configuration in which hollow needle 436 extends through septum 432 (see, eg, FIG. 15 ). Needle assembly 434 includes hollow needle 436 , cap 438 , guide element 440 , and spring 442 . In the illustrated embodiment, cap 438 is configured to couple needle assembly 434 to container assembly 412 . Needle assembly 434 may be coupled to container assembly 412 using any suitable method. For example, in the illustrated embodiment, the cover 438 is configured to receive the first end of the container assembly 412 and utilize a complementary snap-fit feature of the cover 438 and the container assembly 412 to retain the received portion. Guide member 440 includes a receiving slot 444 configured to slidably receive and interface lid 438 and a portion of container assembly 412 . Two opposite ends of the spring 442 are respectively coupled with the end wall 446 of the receiving groove 444 and the cover 438 . In the first configuration, the spring 442 is in an unbiased configuration and maintains the illustrated separation between the cover 438 and the end wall 446 of the receiving slot 444, thereby positioning the hollow needle 436 in a diagram relative to the septum 432. location. The guide element 440 has an outer surface 448 and an outer end wall surface 450 .

FIG. 14 shows the cartridge 430 partially inserted into the inhaler 440 . When the cartridge 430 is inserted into the receiving slot 448 , the cartridge 430 remains in the first configuration in which the hollow needle 436 does not extend past the septum 432 until the end wall outer surface 450 contacts the protruding stop 52 .

FIG. 15 shows the cartridge 430 fully inserted into the inhaler 40 . In the illustrated configuration, the guide element 440 is in contact with the protruding stop 52, and the container assembly 412 has been urged toward the guide element 440, thereby partially compressing the spring 442 and causing the sharp end of the hollow needle 436 to be inserted through the septum 432. . The force of the spring 442 keeps the guide element 440 in contact with the protruding stop 52 , thereby fixing the position of the injection end of the hollow needle 436 relative to the vibratable membrane 64 of the aerosol generator 44 . The end member may serve to retain the cartridge 430 inside the inhaler against the force applied to the container assembly 412 by the compressed spring 442 . The compressed spring 442 maintains the guide element 440 in contact with the protruding stop 52 , thereby maintaining the preferred predetermined position of the injection end of the hollow needle 436 relative to the vibratable membrane 64 .

Inhaler 40 may include a suitable actuator for displacing piston 420 relative to container 418 to eject a desired preselected dose of liquid medicament from container 418 through the ejection end of hollow needle 436 . For example, the end member and housing 42 may form a pressurizable container into which air may be injected to displace the piston 420 towards the guide element 440 . As another example, the piston 420 may be controllably displaced toward the guide element 440 using an actuation mechanism coupled to or acting through the end member.

In use, the user inhales from the mouthpiece 60 while the aerosol generator 44 aerosolizes a dose of liquid medicament ejected from the spray end of the hollow needle 436 with corresponding actuation of the piston 420 . Housing 42 includes one or more air inlets 68 and a restrictor array 70 by which air is directed into mixing chamber 72 for mixing with the aerosolized liquid drug dose prior to inhalation by the user.

Accordingly, the specification and drawings are to be regarded as illustrative rather than restrictive. It will, however, be evident that various modifications and changes can be made in the present disclosure without departing from the broader spirit and scope of the disclosure as set forth in the claims.

Other variations are within the spirit of the disclosure. Thus, while the disclosed technology is capable of various modifications and alternative constructions, certain illustrated embodiments thereof are shown in the drawings and have been described above in detail. It should be understood, however, that there is no intent to limit the disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the disclosure as defined in the appended claims things.

In the context of describing the disclosed embodiments (particularly in the context of the appended claims), use of the terms "a" and "an" and "the" and similar referents in this context should be understood to include the singular and plural, unless otherwise indicated herein or the context clearly indicates otherwise. The terms "including", "having", "comprising" and "containing" are to be construed as open-ended terms (ie, meaning "including but not limited to") unless otherwise stated. The term "connected" should be understood as being partially or completely contained within, attached to, or connected together, even if there is something intervening. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually indicated herein. statement. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly indicated by context to the contrary. The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate embodiments of the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No term in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

Disjunctive expressions, such as the phrase "at least one of X, Y, or Z," unless specifically stated otherwise, are intended to be understood in context to be used generally to mean that an object, term, etc. may be X, Y or Z, or any combination thereof (eg, X, Y, and/or Z). Thus, such disjunctive language is generally not intended and should not mean that certain embodiments require at least one of X, at least one of Y, or at least one of Z to be present each.

Preferred embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such modifications as appropriate, and the inventors intend that the disclosure may be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly indicated by context.

All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference as if each individual reference were individually and specifically incorporated by reference and were set forth in their entirety at In this article.

Claims (29)

1. A self-piercing liquid medicine box, comprising: Containers for storing liquid medicines; a septum configured to seal the first end of the container; A needle assembly coupled to the first end of the container, the needle assembly comprising a hollow needle and capable of being configured in a first configuration wherein the hollow needle does not extend through the septum and wherein the hollow needle extends through the septum reset between the second configurations of ; and and a piston sealing the second end of the container, the piston being repositionable relative to the container to selectively eject a volume of liquid medicament from the container through the hollow needle. 2. The cartridge of claim 1, wherein the needle assembly includes a cap configured to couple the needle assembly with the container. 3. The cartridge of claim 2, wherein the cover has an aperture configured to accommodate a portion of the needle assembly during resetting the needle assembly from the first configuration to the second configuration. The hollow needle and the movement of the hollow needle. 4. The cartridge of any one of claims 1 to 3, wherein the needle assembly further comprises a guide element configured to: supporting the hollow needle in a fixed position and orientation relative to the guide element; Movement of the hollow needle relative to the container is guided during resetting of the needle assembly from the first configuration to the second configuration. 5. The box of claim 4, wherein the guide element defines a receiving groove configured to receive the lid and a portion of the container and to communicate with the lid and the portion of the container. At least one of the butt joints thereby constrains relative movement between the container and the guide element to parallel translation of the hollow needle. 6. The cartridge of claim 4, wherein the needle assembly further comprises a spring element for biasing the needle assembly in the absence of displacement of the container relative to the guide element in the first configuration. 7. The cartridge of claim 4, wherein the end of the hollow needle from which the liquid medicine is ejected protrudes by a predetermined controlled distance from the end face of the guide member. 8. The cartridge of claim 7, further comprising a removable cover for interfacing with the needle assembly and enclosing the protruding end of the hollow needle. 9. A cartridge as claimed in any one of claims 1 to 8, wherein the hollow needle is coated to prevent microorganisms from entering the hollow needle and the container. 10. The cartridge of claim 9, wherein the hollow needles are coated with silver. 11. The cartridge of any one of claims 1 to 10, further comprising a filter configured to prevent microorganisms from entering the container. 12. A cartridge as claimed in any one of claims 1 to 11, wherein fluid is ejected from the cartridge in controlled doses by controlled movement of the piston. 13. The cartridge of claim 12, wherein the size of each of the controlled doses is set by an external controller. 14. The cassette of claim 12, wherein the cassette contains multiple doses of medicament, and the medicament is deliverable from the cassette in separate doses. 15. An atomization system comprising: a housing defining a mouthpiece, the housing comprising a receiving slot configured to at least partially receive a cartridge as claimed in any one of claims 1 to 14 and to interface with the needle assembly so as to resetting the needle assembly from the first configuration to the second configuration during insertion of the cartridge into the receptacle; an aerosol generator disposed in the housing and comprising a vibratable membrane having a front and a back, and a vibratable element for vibrating the membrane; An actuator for repositioning the piston relative to the container for dispensing a dose of the drug via the hollow needle to the back of the vibratable membrane. 16. The system of claim 15, wherein the housing further comprises: a mixing chamber in fluid communication with the front face of the vibratable membrane and the mouthpiece; and One or more air inlets are in fluid communication with the mixing chamber and are configured to introduce air into the mixing chamber in response to user inhalation through the mouthpiece. 17. The system of claim 16, further comprising an array of air flow restrictors having a greater resistance to air flow than said one or more air inlets and positioning said mixing chamber in relation to said One or more air inlets are in fluid communication. 18. The system of claim 17, wherein air flowing through the mixing chamber in response to user inhalation through the mouthpiece is laminar and surrounds a dose of drug aerosolized by the vibratable membrane , thereby preventing contact between the nebulized drug and the surrounding surfaces of the mixing chamber. 19. The system of claim 17, further comprising a pressure port connected to a pressure sensing system, wherein patient inhalation is detected via the pressure port. 20. The system of claim 17, wherein the array of restrictors includes a plurality of orifices arranged in an annular arrangement. 21. The system of any one of claims 15 to 20, further comprising: one or more processors; a tangible memory storing non-transitory instructions which, when executed by the one or more processors, cause the one or more processors to control the actuator to move the piston relative to the container Reposition until a droplet of the liquid drug is ejected from the hollow needle. 22. The system of claim 21 , wherein the instructions, when executed by the one or more processors, cause the one or more processors to detect when the vibratable membrane has been It is judged that the droplet of the liquid medicine has been ejected from the hollow needle by wetting the ejected liquid medicine droplet. 23. The system of any one of claims 15 to 22, wherein the cartridge is configured to be removed at any time to enable more thorough cleaning of the dispenser. 24. The system of any one of claims 15 to 23, wherein the receptacle is configured such that the cartridge cannot be inserted into the receptacle until the removable cover is removed from the cartridge. 25. The system of any one of claims 15 to 24, wherein the vibratable mesh is coupled to the housing via elastomeric vibration isolators configured to increase the efficiency of the aerosol generator. 26. The system of any one of claims 15 to 25, further comprising an ultraviolet light for providing microbial control between administrations. 27. The system of any one of claims 15 to 26, wherein: the housing forms a pressurizable container; and The actuator applies pressure to the container to reposition the piston relative to the container, thereby dispensing a dose of drug via the hollow needle to the back of the membrane. 28. The system of any one of claims 15 to 27, wherein the actuator mechanically displaces the piston relative to the container, thereby dispensing a predetermined desired amount of the liquid medicine. 29. The system of claim 28, wherein the actuator further includes an adjustable metering mechanism operable to allow only a quantitative repositioning of the piston relative to the container for dispensing Quantitative said liquid medicine.